S. aureus is the single most common cause of both systemic and local infections in the drug user population. Despite its recognized importance as a pathogen, surprisingly little is known about factors that predispose drug users to these overwhelming infections. Drug users appear to have a high staphylococcal colonization rate and are believed to become infected with the strains they carry. This proposal will integrate a molecular, epidemiologic analysis of staphylococcal colonization and subsequent infection in this high risk population with a biologic investigation of the pathogenesis of this process. This study will be performed using a cohort of drug users presently followed at the Montefiore Substance Abuse Treatment Program. Examining the basis for staphylococcal colonization and the patterns of carriage in a well defined cohort, will provide an ideal model for understanding the epidemiology and biology of these infections. Our specific aims include the following. 1. Define the demographic features of the drug user population that may influence staphylococcal colonization and infection. These include: 1) the nature and frequency of drug use; 2) the role of sex, age, ethnicity and race; 3) the contribution of HIV infection and disease; and 4) the impact of other medical problems, antibiotic use or intercurrent hospitalization. 2. Compare staphylococcal isolates collected from the drug user cohort and the hospitalized drug users. The DNA profiles of these strains will be determined. The nature and persistence of colonizing strains will be defined, and compared with those causing infection. Linkage of particular colonizing or disease-producing strains with antibiotic resistance or other virulence determinants will be pursued. 3. Examine the biologic features that influence colonization in vitro. The biology of S. aureus nasal colonization will be investigated using the staphylococcal strains collected from controls and the drug user groups. The studies will examine both strain and host specific features that may influence colonization or infection. The increasing problem of multidrug-resistant staphylococci has added new urgency to the need for alternative approaches to the prevention of these life-threatening diseases. In order to develop these alternatives, we must first understand the strain and host determinants that play a role in this process.